Solubility, drug preformulation

Serajuddin, A.T.M., Sheen, P.C., Mufson, D., Bernstein, D.F., and Augustine, M.A., Preformulation study of a poorly water soluble drug, alpha-pentyl-3-(2-quinolinyl-methoxy) benzenemethanol selection of the base for dosage form design, /. Pharm. Sci., 75, 492, 1986. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

Solubility is highly influenced by the solid-state form (e.g., crystalline or amorphous) of the drug. Rigorous solubility studies using the final solid form (i.e., salt form or crystal form) as a function of temperature (i.e., 25 and 37°C) and pH (range 1 to 7.5) are conducted during preformulation. Solubility in nonaqueous solvents is also screened. Solubility in simulated gastrointestinal fluids is also important. 

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

Drug solubility is one of the physicochemical parameters that receives lots of attention during preformulation testing. In the initial stages, solubility studies are usually kinetically determined, where the drug is placed in contact with the solvents and then the solubility is assessed using turbidometric methods almost instantaneously. 

Drugs may also have more than two pKa values, such as polyprotic or polybasic compounds (e.g., minocycline), and such drugs exhibit a complex pH solubility profile. It is essential to know per se pH of the drug solution during preformulation studies. The pH is measured or theoretically calculated if the pKa and drug concentration C are known. The pH of a weak acid or the salt of a weak base and a strong acid can be calculated using the equation... 

Hence it is important to study this effect during preformulation by testing the solubility of the salt in the presence and absence of sodium chloride. Although salts do not alter the pharmacological activity of the drug, safety is an important consideration in the selection of salts. From this perspective, salts are treated as a new molecule by the FDA. The safety of the salt is evaluated with respect to its route of administration and dose of the drug [37],... 

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

An objective of preformulation scientist is to determine the equilibrium solubility of a drug substance under physiological pH to identify the BCS class of drug candidate for further development. For BCS classification the test conditions are strictly defined by the FDA. The pH solubility profile of the test drug substance should be determined at 37°C in aqueous media with a pH in the range of 1-7.5. Standard buffer solutions described in the USP are considered to be appropriate for use in these studies. A number of pH conditions are used bracketing the pKa value for the respective test substance. For example, for a drug with a Ka of 5, solubility should be determined at... 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

By the time an active pharmaceutical ingredient (API) is made available to an analytical chemist in the formulation development group, most or all of the physical characteristics of an API has already been studied and the information should be available in some sort of a report from the drug substance group or preformulation group. Some of the key parameters that an analytical chemist in formulation development requires from such a report are the solubility and solution stability. 

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